Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy

Abstract

The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice

“…In the knock-in AR113Q SBMA mice, a progressive shift from glycolytic to oxidative fibres has also been reported (Rocchi et al, 2016). Furthermore, SBMA patients also exhibit switching in muscle fibre type from glycolytic to oxidative fibres (Yamada et al, 2016). In addition, as early as 6 months of age, ubiquitin inclusions were observed, predominantly within very fast twitch type 2B TA and EDL muscle fibres.…”

Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease

“…Muscles of SBMA subjects demonstrate glycolytic-to-oxidative switching over the course of the disease. 26 Remarkably, disease progression in AR113Q mice also results in a progressive shift from glycolytic to oxidative fibres, which precedes muscle atrophy and may be due to the preferential vulnerability of glycolytic fibres with respect to oxidative fibres. 27 Furthermore, lipidomic analyses revealed an altered lipid composition in the muscle of knock-in mice compared with control animals.…”

Study protocol for the MEXiletine hydrochloride administration trial: a placebo-controlled, randomised, double-blind, multicentre, crossover study of its efficacy and safety in spinal and bulbar muscular atrophy (MEXPRESS)

“… 33 We will evaluate muscle mass with dual-energy X-ray absorptiometry (DXA) using fan-beam technology (Discovery A; Hologic, Bedford, Massachusetts, USA). The sum of the appendicular lean soft tissue mass measured with DXA has been validated by the skeletal muscle mass measurement using MRI and CT. 34–36 We will also evaluate the 36-Item Short Form Health Survey, 37 Individualised Neuromuscular Quality of Life questionnaire, 38 IVR diary, 16 39 respiratory function values (vital capacity, forced vital capacity, percentage of forced expiratory volume in one second, peak expiratory flow, respiratory resistance and flow–volume curve) 40 and blood tests (complete blood count, electrolytes, creatinine, creatine kinase, 41 42 aldolase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and testosterone).…”